The rationally-designed immunogens developed in Projects 1 and 2 and produced in Core B will be tested in vivo in this Core for their ability to induce Abs in rabbits and/or non-human primates that are broadly reactive against HIV-1 isolates of different clades. The experiments will utilize an established DNA prime/protein boost protocol in which the DNA priming constructs will include Env genes, and the boosting constructs will consist of the V2-scaffold immunogen(s) and/or the QNE-scaffold immunogen(s). The work in Core C is divided into two specific aims: Aim 1. To induce broad, potent, and long-lasting functional Ab responses in rabbits using rationally designed V2-scaffold immunogens as protein boosts subsequent to priming with Env genes. V2/V3 QNE-scaffold immunogens can only be tested in non-human primates because a) rabbits have not been shown to produce Abs carrying CDR H3 regions of the length needed for QNE-specific Abs, and b) it is not know if rabbits possess the immunoglobulin genes required to encode these Abs, whereas we have shown that SHIV-infected NHPs can produce QNE Abs. Thus, the V2/V3 QNE-scaffold immunogens will be tested in NHPs. In contrast, the V2-scaffold immunogens will first be tested in rabbits. To qualify for testing in NHPs, the V2-specific Ab responses achieved in rabbits will need to meet one or more of the following criteria: (a) Induction of Abs that neutralize the majority of Tier 1 pseudoviruses in the TZM.bl assay with titers better than 1:50; (b) Induction of Abs that neutralize >25% of Tier 2 pseudoviruses from at least two clades with titers better than 1:20 in at least one of the three neutralization assays used; (c) Induction of Abs that mediate additional anti-viral functions, and/or display neutralizing or other anti-viral activities against SHIVSFI62P3- Aim 2. To induce broad, potent, long-lasting and protective Ab responses in non-human primates using rationally designed V2- and/or V2/V3 QNEscaffold immunogens as protein boosts subsequent to priming with Env genes.